Regulation of Masking and Circadian Rhythm Phase

描述（由申请人提供）：负掩蔽是当哺乳动物暴露于光时发生的夜间自发活动的抑制。一方面，它被认为是昼夜节律评估的不便之处，因为它可能掩盖潜在的事件。另一方面，掩蔽已被研究为它自己的缘故，并且已知是由介导光诱导相移的相同类别的光感受器介导的。事实上，尽管光致掩蔽被认为与光致相移有根本不同，但真正说明这个问题的唯一数据来自两项视交叉上核（SCN）病变研究。其中更仔细的支持这样一种观点，即SCN对于每一种反应都是必要的，而且通过外推，SCN是两者的起源。这一观点也与大量数据一致，这些数据表明光和运动活动可以相互抑制对方对昼夜节律相位的影响。这项提议使用小鼠来解决昼夜视觉系统的两个基本问题。行为分析将允许比较毫秒光刺激（数量、强度、闪光间隔）对掩蔽和相移的影响。通过类比的论点将支持这两种反应类似地由光调制的命题，因此，可能是由相同的输入途径和视网膜受体核（SCN）控制。转基因小鼠（黑视蛋白缺陷（Opn 4-/-）和视杆/视锥退化（rd-/rd-））将用于消除各种光感受器的功能，并确定相同光感受器介导掩蔽和相移的程度。他们还将确定ipRGC是否是介导相移和掩蔽的SCN的光感受途径的必要部分，即使这些细胞不含黑视素色素。结论性研究将使用化学、刀切、损伤和束追踪方法来明确确定SCN是否介导相移和掩蔽，以及相同的大脑区域或通路是否参与光诱导睡眠现象。这是特别重要的，因为迄今为止，没有解剖学或生理学证据表明，光对掩蔽，相移或光诱导的睡眠的影响可以在SCN细胞水平上区分。这些结果有望大大提高我们对光输入通路介导昼夜节律相移、掩蔽和光诱导睡眠的解剖学、生理学和功能的理解。使用非常短暂的（毫秒）光刺激将提供一种新的方法来研究调节这三种行为的过程。公共卫生相关性生理和行为昼夜节律通过涉及几种不同感光器类型的通路与光信号同步。该项目利用新颖的光刺激，新的测试程序和小鼠模型来辨别哪些光感受器，神经通路和大脑区域有助于节奏计时以及光抑制运动和诱导睡眠的能力。研究还旨在促进对视觉健康和正常功能的基本了解。为了开发对患有诸如延迟相睡眠综合征、季节性情感障碍、不适当的睡眠时间或其他身体节律等问题的人的临床护理方法，有必要了解光刺激如何作用于和调节昼夜节律系统，以及它如何与睡眠和觉醒相关。

DESCRIPTION (provided by applicant): Negative masking is the suppression of nocturnal locomotor activity that occurs when a mammal is exposed to light. On the one hand, it has been considered to be either an inconvenience for circadian rhythm assessment insofar as it can obscure underlying events. On the other, masking has been studied for its own sake and is known to be mediated by the same classes of photoreceptors that mediate light-induced phase shifts. In fact, although light-induced masking has been considered to be fundamentally different from light-induced phase shifts, the only data that actually speak to the issue come from two suprachiasmatic nucleus (SCN) lesion studies. The more careful of these supports the view that the SCN is necessary for each response and, by extrapolation, is the origin of both. This view is also consistent with substantial data showing that light and locomotor activity can mutually inhibit each other's effect on circadian phase. This proposal uses mice to address two issues fundamental to the circadian visual system. Behavioral analysis will allow comparison of the effects of millisecond light stimuli (number, intensity, inter-flash interval)on masking and phase shifts. An argument by analogy will be made in support of the proposition that these two responses are similarly modulated by light and, therefore, likely to be controlled by the same input pathway and retinorecipient nucleus (SCN). Transgenic mice (melanopsin deficient (Opn4-/-) and rod/cone degenerate (rd-/rd-)) will be used to eliminate function the various photoreceptors and determine the extent to which masking and phase shifts are mediated by the identical photoreceptors. They will also determine whether ipRGCs are a necessary part of the photoreception pathway to the SCN that mediates both phase shifts and masking, even if such cells do not contain melanopsin photopigment. Concluding studies will use a chemical, and knife cut, lesion and tract tracing methods to explicitly determine whether or not the SCN mediates both phase shifts and masking, and whether the same brain regions or pathways are involved in the phenomenon of light-induced sleep. This is particularly important because there is, as yet, no anatomical or physiological evidence that effects of light on masking, phase shifts or light-induced sleep can be distinguished at the level of SCN cells. The results are expected to greatly improve our understanding of the anatomy, physiology and function of the photic input pathway mediating circadian rhythm phase shifts, masking and light- induced sleep. The use of very brief (millisecond) photic stimuli will provide a novel approach for studying processes regulating those three behaviors. PUBLIC HEALTH RELEVANCE Physiological and behavioral circadian rhythms are synchronized to light signals by a pathway involving several different photoreceptor types. This project utilizes novel light stimuli, new test procedures and mouse models to discern which photoreceptors, neural pathways and brain regions contribute to rhythm timing and to the ability of light to suppress locomotion and induce sleep. Studies are also designed to promote basic understanding of visual health and normal function. In order to develop methods of clinical care for persons suffering from such problems as delayed phase sleep syndrome, seasonal affective disorder, inappropriate timing of sleep or other bodily rhythms, it is necessary to understand how photic stimuli act upon, and regulate, the circadian rhythm system, and how it relates to sleep and arousal.